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Journal of Cellular Immunology Review Article

Ca2+/-dependent Protein in Leukemia Development

Changhao Cui2, Chen Wang1, Min Cao1, Xunlei Kang1* 1Center for Precision Medicine, Department of Medicine, University of Missouri, 1 Hospital Drive, Columbia, Missouri 65212, USA 2School of Life Science and Medicine, Dalian University of Technology, Liaoning 124221, China

*Correspondence should be addressed to Xunlei Kang; [email protected]

Received date: March 18, 2021, Accepted date: April 20, 2021

Copyright: © 2021 Cui C, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Ca2+/ calmodulin (CaM) signaling is important for a wide range of cellular functions. It is not surprised the role of this signaling has been recognized in tumor progressions, such as proliferation, invasion, and migration. However, its role in leukemia has not been well appreciated. The multifunctional Ca2+/CaM-dependent protein kinases (CaMKs) are critical intermediates of this signaling and play key roles in cancer development. The most investigated CaMKs in leukemia, especially myeloid leukemia, are CaMKI, CaMKII, and CaMKIV. The function and mechanism of these kinases in leukemia development are summarized in this study.

Keywords: CaMKII, CaMKI, CaMKIV, Leukemia, ITIM containing receptor, Signaling pathway, Therapeutic target

Introduction The classic CaMKs include CaMKI, CaMKII, and CaMKIV, each of which has multiple isoforms. They Calcium (Ca2+) is an intracellular universal second are multifunctional serine/threonine protein kinases messenger that regulates a variety of cellular processes. that regulate the development and activity of different Many biological processes, including transcription, kinds of cell types through a variety of substrates [6-8]. cell cycle, migration, and apoptosis, are affected by changes The structure of CaMKs is critical for their activation in intracellular Ca2+ signaling [1,2]. Disruption of normal and regulation (Figure 1). Similarly, they all have an Ca2+ signaling can cause tumorigenic phenotypes [3]. N-terminal domain, followed by a regulatory domain (consisting of Ca2+/CaM binding domain (CBD) 2+ Ca signaling works by forming a complex with calmodulin and auto-inhibitory domain (AID)). The ADP/ATP binding (CaM), a 148-amino-acid protein that transduces signals site locates between the small and large lobes of CaMKs’ 2+ 2+ in response to intracellular Ca elevation. Ca binding kinase domains. CaMKII, on the other hand, has a special significantly alters CaM’s conformation and enhances self-association domain at the C-terminus that allows it to its affinity for a wide range of CaM-binding proteins. form holoenzymes [8-10]. Since the discovery of CaM in 1970 as a Ca2+ regulator, there have been over 80 Ca2+/CaM-regulated protein CaMKs have a special phosphorylation-dependent kinases described [4]. However, based on their substrate mechanism for the regulation of kinase activity. specificity, not all CaM-regulated kinases are Ca2+/CaM- dependent protein kinases (CaMKs). For example, the The changes in intracellular Ca2+ concentration trigger once called CaMKIII is now termed eukaryotic elongation Ca2+ binding to the ubiquitously expressed CaM induces factor 2 (eEF2) kinase, due to containing a small number a conformational transition, which sparks its binding to of substrates [5]. CBD of CaMKs. The adjacent AID will then be released, triggering CaMK activation. The difference is, for CaMKII, Structure and Activation the Thr-286 residue in the regulatory domain is auto-

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Figure 1: Schematic diagrams of CaMKII, CaMKI, and CaMKIV. The subunit structures with key residues involved in their regulation by phosphorylation (red font). See text for details. phosphorylated before kinase activation. While CaMKI/ of prostate cancer cells [18]. All these studies indicate CaMKIV is phosphorylated by an upstream kinase, CaMKs may be involved in different signaling pathways to CaMKK at Thr-177 and Thr-196 residue, respectively, manipulate cancer development. both located in the kinase domain. Despite the fact that CAMKK activates both CaMKI and CaMKIV, their distinct By using a variety of CaM antagonists or CaMKs specific subcellular distributions after phosphorylation, cytosolic inhibitors, the researchers have corroborated the roles of for CaMKI versus nuclear localization for CaMKIV, can CaMKs in a multitude of tumor types, which can prevent allow them to play different roles in distinct cellular cell growth, invasiveness, and /or metastasis [19-24]. For settings [9,11]. detail reviews on the role of CaMKs in cell migration and cancer metastasis, see [3,25-27]. CaMKs in Cancer Development Relevance to Leukemia Effective cell migration, which is critical for cancer metastasis, requires proper Ca2+ signaling control. Many In comparison to a large number of studies on CaMKs in CaMKs including CaMKI, CaMKII, and CaMKIV play a role neurology and solid tumors, research on CaMKs’ function in cell-migration-related cytoskeleton dynamics. Thus, the in controlling hematopoiesis and leukemia has been scarce. role of CaMKs in tumor cell invasiveness and metastatic Leukemia diseases are not classified as metastatic cancer. potential is well implicated [3,12]. Because they are thought to already be widespread when they are diagnosed. Below, we discuss the role of CaMKs in Iwatsubo’s group found that store-operated Ca2+ entry leukemia development based on work of ours and others. regulates melanoma proliferation and cell migration Emphasis is given to CaMK’s function in myeloid leukemia, by activating CaMKII. Further, they demonstrated that as well as the signaling pathway they are involved. CaMKII inhibition suppressed MAPK signaling pathway, which can inhibit human melanoma cell migration and Using the TCGA database of AML patients, we conducted metastasis in the lungs [3,13,14]. Interestingly, the CaMKII/ an in silico study of the relationship between gene MAPK signaling axis was also linked to colon cancer, expression and overall survival in AML patients. (https:// inhibiting CaMKII decreased cancer cell proliferation, tcga-data.nci.nih.gov/tcga/). The expression of most migration, and invasion [15]. The CaMKK pathway has CAMKs analyzed showed a negative correlation between been shown to promote cerebellar granule precursor expression and patient survival, which including CAMKI, migration and differentiation during normal cerebellar CAMK2A, CAMK2D, CAMK4, CAMKK2 [28,29]. These development via CaMKIV [16], while CaMKK/CaMKI results suggest that many CaMKs directly support human cascade regulates basal medulloblastoma cell migration leukemia cell growth. Here, we summarize the leukemia- via Rac1. In addition, pharmacological CaMKK inhibition related roles of individual CaMKs. blocks both estrogen-induced Rac1 activation and medulloblastoma migration [17]. These findings indicate CaMKII that the differential regulation of CaMKs in normal and malignant scenarios is context-dependent. McDonnell’s CaMKII is the most widely studied CaMKs, which consists group found that CaMMKβ is highly expressed in the of four homologous (CaMKIIa, CaMKIIb, CaMKIIg, and prostate and is further elevated in prostate cancers. Using CaMKIId) [1]. CaMKII’s autophosphorylation is one of its cellular models of prostate cancer, they demonstrated that most important functional characteristics which means CaMKK/AMPK regulates androgen-dependent migration that its activation is self-contained and less influenced

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Cui C, Wang C, Cao M, Kang X. Ca2+/calmodulin-dependent Protein Kinases in Leukemia Development. J Cell Immunol. 2021; 3(3): 144-150. by Ca2+ concentration or calmodulin regulation. CaMKII of human CAMK1 mRNA expression in 43 human AML makes up about 1% to 2% of total brain protein, and samples showed that it is highly expressed in M5 AML numerous studies have shown that it plays an important cells [28,43]. Moreover, CaMKI is greatly expressed role in controlling neuronal cell growth and function [26]. in AML LSCs in mouse MLL-AF9 model. Gain-of- function and loss-of-function analyses of CaMKI in AML Although aberrant activation of CAMKII has been linked cells in vivo proved that CaMKI is essential for the growth to different hematopoietic malignancies [30,31], most of human and mouse AML cells [28,29]. The mechanistic studies focus on one of its isoforms, CaMKIIg, and its role studies indicated CaMKI participates in the Inhibitory in myeloid leukemia. CaMKIIg is preferentially expressed leukocyte immunoglobulin-like (ITIM) receptors signaling in myeloid cells [32,33]. Furthermore, the activation of axis in leukemia development by the recruitment of SH2 CaMKIIg is greatly increased in leukemia stem/progenitor domain-containing phosphatase1 (SHP-1). The activated cells but not in normal hematopoietic cells [34-36]. By CaMKI can be transported into the nucleus [44] and phosphorylating and inhibiting the transcriptional function activate the downstream transcription factor cyclic AMP of retinoic acid receptors (RARs), CaMKIIg prevents the element-binding protein (CREB) in AML cells [29]. CREB differentiation of myeloid leukemia cells. Coordinately, is one of the well-known targets of CaMKs in hematopoietic CaMKII inhibitors improve the differentiation of myeloid cells, which can be phosphorylated and activated by CaMKs leukemia cells [32]. This finding was further extended to [45,46]. This novel signaling pathway identified in AML non-retinoic acid responsive myeloid leukemia cells, which stem cells may represent a target for AML treatment [47]. demonstrates that CaMKIIg plays a critical and central role in controlling the proliferation of a broad range of myeloid CaMKIV leukemia cells [33]. The mechanistic studies showed that CaMKII activation induced by different stress contributes CaMKIV is encoded by the CAMK4 gene. Alternative to mitogenic signaling and promotes the proliferation of processing yields two distinct isoforms (CaMKIVa and leukemia cells [14,37]. Strikingly, Huang’s group proved CaMKIVb) [48]. The CaMKIV expression pattern is that CaMKIIg is a key regulator of leukemia stem cells similar to other CaMKs, with primarily being expressed in chronic myeloid leukemia (CML) [35]. The findings in in the brain, however, CaMKIV is also present in mouse CML leukemia model and human CML patients hematopoietic cells, testes and ovaries [49-52]. CaMKIV indicate that CaMKIIg could be a critical regulator in the has been implicated in the regulation of homeostatic progression of CML blast crisis, and they reveal a novel plasticity, neurite outgrowth, fear memory, immune and mechanism by which CaMKIIg promotes leukemia stem inflammatory responses [1,53]. cell (LSC) self-renewal by inhibiting nuclear p27Kip1 and reawakening dormant LSCs [34,38]. The signaling studies CaMKIV have been shown to play a significant role in both AML and CML revealed that CaMKIIg acts as an in hematopoietic physiology and pathology in a few important regulator of multiple cancer-related signaling studies. CaMKIV/CREB/BCL-2 signaling is required pathways including NF-κB, Wnt/b-catenin, p42/p44/ for hematopoietic stem cell (HSC) activity. CaMKIV is MAPK, and Stat3/5 networks [32,35]. The supportive correlated with increased apoptosis and proliferation of role of CaMKIIg in the development and progression of HSCs in vivo and in vitro [50]. We also found that, in + myeloid leukemia was verified by the treatment of specific human cord blood CD34 cells, Angptl binding to ITIM inhibitors or by depletion of CaMKIIg [14,32,33,35-37]. In receptors can trigger phosphorylation of CaMKIV [54]. summary, inhibition of CaMKIIg activity may be beneficial CaMKIV is also a key player in the imbalance between Treg in the treatment of myeloid leukemia. and Th17 cells. CaMKIV contributes to the reduction of IL-2 and the restriction of Treg cells in patients with SLE [55]. CaMKI Since IL-2 has been shown to inhibit Th17 differentiation, CaMK4 inhibition possibly promotes Th17 differentiation Similar to CaMKII, CaMKI is multifunctional kinases that indirectly [56,57]. Although HSCs in CAMKIV-knockout have been linked to neuronal plasticity and gene regulation mice showed only mild defects [50], The loss of function of [9]. In human, the CaMKI family consists of four members, LILRB2/PirB or CaMKIV, on the other hand, is detrimental each of which is encoded by a different gene: CAMK1, to AML growth. Importantly, inhibiting CaMKIV kinase PNCK, CAMK1G and CAMK1D, which generate CaMKIa, activity or deleting CaMKIV significantly reduced AML CaMKIb, CaMKIg, and CaMKId, respectively [39]. stem cell activity. We discovered that phosphorylation of CREB is important downstream of CaMKIV signaling in It is reported that the isoforms of CaMKI are ubiquitously AML cells using a rescue assay. Our findings showed that expressed at low levels [40], and expressed at high levels CaMKIV signaling promotes AML cell self-renewal and in several brain regions [41,42]. Interestingly, we found inhibits apoptosis [28]. As a result, inhibiting CaMKIV is that CaMKI protein is well detected in both normal likely to be successful in treating leukemia with limited hematopoietic cells and AML cells. An in silico analysis hematopoietic system side effects.

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Concluding Remarks and Perspectives may be due to the relative high expression of CAMKs in myeloid cell lineage. Because inhibition of the expression Targeted therapy is an effective cancer treatment and/or activity of CaMKs directly blocks leukemia cell technique that has seen a lot of success in clinical trials growth and activity, and suppresses tumorigenesis and [58]. Currently, many of the clinically used targeted cancer leukemia development, but does not much disturb normal drugs are tyrosine kinase inhibitors. However, even though development, CaMKs may represent ideal targets for these medications have extraordinary effectiveness at first, treating leukemia. Since there are many different CaMKs, drug resistance emerges later, limiting their utility [59]. which can express differently in diverse leukemia types or Finding new drug targets and developing new targeted subtypes. It is fascinated to see how these CaMKs interact anticancer agents have accordingly become urgent for individually and in combination in cancer cells. For drug discovery and development. Because the different example, in leukemia cell lines (U937), inhibiting CaMKII structure between tyrosine kinases and serine-threonine activity causes an upregulation of CaMKIV mRNA and kinases, drugs that target CaMKs are less likely to protein. CaMKIV expression, on the other hand, inhibits modulate conventional kinases and, in theory, do not have CaMKII autophosphorylation and activation, as well as or trigger cross-resistance with traditional kinase drugs. G0/G1 cell cycle arrest, which inhibits cell proliferation The CaMK family members, particularly CaMKII, CaMKI, [38]. This data indicates that CaMKII suppresses CaMKIV CaMKIV, are appealing anti-cancer targets because they expression to promote leukemia cell proliferation. are overexpressed in myeloid leukemia as compared to normal blood cells and play a critical role in leukemia cell Blocking CaMKs signaling in conjunction with standard proliferation, differentiation and self-renewal. therapies may be an effective method for destroying leukemia cells. In light of the tremendous importance In contrast to studies in other forms of tumors, there of CaMKs signaling in leukemia development, it will be has been very little research into the role of CaMKs in critically important to identify more components involved leukemia. Our review reveals that most of these limited in this signaling (Figure 2). Besides ITIM containing studies focus on myeloid leukemia diseases, which receptors, whether there are any other upstream signaling

Figure 2: Both calcium channel signaling and ITIM containing receptor signaling are involved in leukemia progression by binding to and activating the Ca2+/calmodulin dependent family. Intracellular Ca2+ and CaM level is upregulated in leukemia cells. The activated CaMKII will further activate different oncogenic signaling in leukemia cells, such as p42/44, NF-kB, Stat3/5, b-catenin. The signaling will translocate to the nuclear by their downstream transcription factors, such as TCF, CREB. CaMKII has also been reported to inhibit the activation of RAR to block the differentiation. ITIM containing receptors can recruit CaMKI/IV directly or indirectly by phosphatase SHP-1. CaMKI/IV can be activated by classical CaMKK pathway. The coordinated regulation of CaMKI/IV by Ca2+ signaling and ITIM containing receptor signaling is unknown. The activated CaMKI/IV then induce phosphorylation of the transcription factor CREB. Finally, these signaling pathway will activate downstream to initiate the regulation of self-renewal, survival and differentiation of leukemia cells.

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Cui C, Wang C, Cao M, Kang X. Ca2+/calmodulin-dependent Protein Kinases in Leukemia Development. J Cell Immunol. 2021; 3(3): 144-150. involved? Our studies have identified CREB as the major 8. Fujisawa H. Regulation of the activities of downstream signaling that are activated by CaMKI/IV. If multifunctional Ca2+/calmodulin-dependent protein there is another transcriptional factor that is crucial for kinases. J Biochem. 2001;129(2):193-9. leukemia development and controlled by CaMKI and/or CaMKIV need to be further investigated. For CaMKIIg, 9. Wayman GA, Tokumitsu H, Davare MA, Soderling TR. how consequential phosphorylation of several target Analysis of CaM-kinase signaling in cells. Cell Calcium. substrates dynamically cooperates to modulate leukemia 2011;50(1):1-8. cell proliferation or activity. These future directions may help further to clarify the role of CaMKs in leukemia 10. Swulius MT, Waxham MN. Ca(2+)/calmodulin- development. dependent protein kinases. Cellular and Molecular Life Sciences : CMLS. 2008;65(17):2637-57. Acknowledgements 11. Bayer KU, Schulman H. CaM Kinase: Still Inspiring at We would like to thank the NIH (R37CA241603) for 40. Neuron. 2019;103(3):380-94. generous support. We regret that we have been unable to cite many relevant primary references due to space 12. Brzozowski JS, Skelding KA. The Multi-Functional limitations. Calcium/Calmodulin Stimulated Protein Kinase (CaMK) Family: Emerging Targets for Anti-Cancer Therapeutic Disclosure of Potential Conflicts of Interest Intervention. Pharmaceuticals (Basel). 2019;12(1).

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